AVP is a hormone known for its antidiuretic effect and its effect in regulating arterial pressure. It stimulates several types of receptor: V1 (V1a, V1b), V2. These receptors are located in particular in the liver, vessels (coronary, renal, cerebral), platelets, kidney, uterus, adrenal glands, pancreas, central nervous system and pituitary gland. AVP thus exerts cardiovascular, hepatic, pancreatic, antidiuretic and platelet-aggregating effects and effects on the central and peripheral nervous system, and on the uterine sphere.
The location of various receptors is described in: S. JARD et al., Vasopressin and oxytocin receptors: an overview, in Progress in Endocrinology. H. IMURA and K. SHIZURNE ed., Experta Medica, Amsterdam, 1988, 1183-1188, and in the following articles: J. Lab. Clin. Med., 1989, 114 (6), 617-632 and Pharmacol. Rev., 1991, 43 (1), 73-108.
More particularly, the AVP V1a receptors are located in numerous peripheral organs and in the brain. They have been cloned in rats and humans and they regulate the majority of the known effects of the AVP: platelet aggregation; uterine contractions; contraction of the vessels; contraction of renal mesangial cells, the secretion of aldosterone, cortisol, CRF (corticotropin-releasing factor) and adrenocorticotrophic hormone (ACTH); hepatic glycogenolysis, cell proliferation and the main central effects of AVP (hypothermia, memory, anxiety, affiliation and the like).
The adrenocortex is also rich in V1a receptors involved in the production of gluco- and mineralocorticoids (aldosterone and cortisol). Via these receptors, AVP (circulating or synthesized locally) can induce a production of aldosterone with an efficiency comparable to that of angiotensin II (G. GUILLON et al., Endocrinology, 1995, 136 (3), 1285-1295). Cortisol is a potent regulator of the production of ACTH, the stress hormone.
Recent studies have shown that the adrenal glands were capable of directly releasing CRF and/or ACTH via the activation of the V1a and/or V1b receptors carried by the cells of the medulla (G. MAZZOCCHI et al., Peptides, 1997, 18 (2), 191-195; E. GRAZZINI et al., J. Clin. Endocrinol. Metab., 1999, 84 (6), 2195-2203).
The V1a receptors are also a more specific marker for small-cell lung cancers (SCLC) (P. J. WOLL et al., Biochem. Biophys. Res. Commun., 1989, 164 (1), 66-73). Thus, the compounds according to the present invention are obvious diagnostic tools and offer a novel therapeutic approach for controlling the proliferation of these tumours and their detection, even at an early stage (radiolabelling; SPECT, Single Photon Emission Computed Tomography; PET Scan, Positron Emission Tomography Scanner).
The V1b receptors were initially identified in the adenohypophysis of various animal species (rat, pig, cow, sheep and the like) including in humans (S. Jard et al., Mol. Pharmacol., 1986, 30, 171-177; Y. Arsenijevic et al., J. Endocrinol., 1994, 141, 383-391; J. Schwartz et al., Endocrinology, 1991, 129 (2), 1107-1109; Y. de Keyser et al., FEBS Letters, 1994, 356, 215-220) where they stimulate the release of adrenocorticotrophic hormone by AVP and potentiate the effects of CRF on the release of ACTH (G. E. Gdjjes et al., Nature, 1982, 299, 355). In the hypothalamus, the V1b receptors induce a direct release of CRF (Neuroendocrinology, 1994, 60, 503-508) and are, in these various respects, involved in stress situations.
These V1b receptors have been cloned into rats, human and mice (Y. de Keyser, FEBS Letters, 1994, 356, 215-220; T. Sugimoto et al., J. Biol. Chem., 1994, 269 (43), 27088-27092; M. Saito et al., Biochem. Biophys. Res. Commun., 1995, 212 (3), 751-757; S. J. Lolait et al., Neurobiology, 1996, 92, 6783-6787; M. A. Ventura et al., Journal of Molecular Endocrinology, 1999, 22, 251-260) and various studies (in situ hybridization, PCR, Polymerase Chain Reaction, and the like) reveal a ubiquitous location of these receptors in various central tissues (brain, hypothalamus and adenohypophysis, in particular) and peripheral tissues (kidney, pancreas, adrenal glands, heart, lungs, intestine, stomach, liver, mesentery, bladder, thymus, spleen, uterus, retina, thyroid, and the like) and in some tumours (hypophysial tumours, pulmonary tumours and the like), suggesting a broad biological and/or pathological role of these receptors and potential involvement in various diseases.
By way of examples, in rats, studies have shown that AVP, via the V1b receptors, regulates the endocrine pancreas, stimulating the secretion of insulin and glucagon (B. Lee et al., Am. J. Physiol. 269 (Endocrinol. Metab. 32): E1095-E1100, 1995) or the production of catecholamines in the medullo-adrenal which is the seat of local synthesis of AVP (E. Grazzini et al., Endocrinology, 1996, 137 (a), 3906-3914). Thus, in the latter tissue, AVP, via these receptors, is thought to have a crucial role in some types of adrenal pheochromocytomas which secrete AVP and thereby induce sustained production of catecholamines responsible for hypertension resistant to antagonists of the angiotensin II receptors and converting enzyme inhibitors.
The V1b receptors are also considered as a marker for ACTH-secreting tumours such as certain pituitary tumours, certain bronchial carcinomas (SCLC, Small Cell Lung Cancers), pancreatic carcinomas, adrenal carcinomas and thyroid carcinomas, resulting in Cushing's syndrome in some cases (J. Bertherat et al., Eur. J. Endocrinol., 1996, 135, 173; G. A. Wuinert et al., Lancet, 1990, 335, 991-994; G. Dickstein et al., J. Clin. Endocrinol. Metab., 1996, 81 (8), 2934-2941).
The abundant presence of the messenger for the V1b receptors at the stomach and intestinal level suggests an involvement of AVP via this receptor on the release of gastrointestinal hormones such as cholecystokinin, gastrin or secretin (T. Sugimoto et al., Molecular cloning and functional expression of V1b receptor gene, in Neurohypophysis: Recent Progress of Vasopressin and Oxytocin Research; T. Saito, K. Kurosawa and S. Yoshida, ed., Elsevier Science, 1995, 409413).
1,3-Dihydro-2H-indol-2-one derivatives have been described in some patent applications as ligands for the arginine-vasopressin and/or oxytocin receptors: there may be mentioned patent applications WO 93/15 051, EP 636 608, EP 636 609, WO 97/15 556, WO 98/25 901, WO 01/55 130, WO 01/55 134, WO 01/64 668, WO 01/98 295, WO 03/008 407, WO 06/080 574, WO 08/025,735.
International application WO 95/18 105 relates to compounds of formula:
in which in particular:
X represents SO2;
RI, RII, RIII, RIV, RV, RVI and q have different values.
The compounds of formula (A) have affinity for in general the vasopressin and/or oxytocin receptors. In addition, this application describes no example in which the 4-position of the indol-2-one ring is occupied by a nitrogen atom and RIV is still attached at the 3-position of the indol-2-one ring by a nitrogen atom.
In particular 3-[4-[[5,6-dichloro-3-(2-chlorophenyl)-2-oxo-3-[(2-piperidin-4-ylethyl)amino]-2,3-dihydro-1H-indol-1-yl]sulphonyl]phenyl]-1,1-diethylurea (compound α) is described in Example 220 and 3-[4-[[5-chloro-3-(2-chlorophenyl)-6-methyl-2-oxo-3-[(2-piperidin-4-ylethyl)amino]-2,3-dihydro-1H-indol-1-yl]sulphonyl]phenyl]-1-diethylurea (compound β) is described in Example 277 of WO 95/018 105.
Compound a exhibits good affinity for the human V1a receptors for AVP, but also for the human V2 receptors for AVP and the oxytocin receptors; it is not therefore selective for the human V1a receptors for AVP and for the human V1b receptors for AVP.
Compound β exhibits good affinity for the human V1a receptors for AVP, but also for the human V2 receptors for AVP; it is not therefore selective for the human V1a receptors for AVP and for the human V1b receptors for AVP.